Obstructive sleep apnea is characterized by recurrent periods of pharyngeal occlusion during sleep with recognized cardiovascular, respiratory and neurocognitive dysfunction. Current treatment strategies have been designed to either relieve or bypass the site of upper airway obstruction, but are often ineffective or poorly tolerated. In this proposal, we outline a potentially novel approach for treating apneic patients with high flow transtracheal insufflation (hf-TTI), a method for delivering airflow to the trachea through a thin cannula. Based on current understanding of the pathogenesis of upper airway obstruction during sleep, we take advantage of the unique physiologic properties of the upper airways to regulate breathing patterns during hf-TTI administration. Utilizing a Starling resistor model of the upper airways, we will characterize the mechanical and reflex factors that control their properties, and build a conceptual framework for developing new strategies to support ventilation during sleep. In each of three Specific Aims, we explore airflow dynamics through the upper airway during hf-TTI administration and delineate the mechanisms which modulate upper airway collapsibility and outflow resistance. In Specific Aim 1, we will model the biomechanics of the upper airway under (a) steady-state and (b) dynamic hf-TTI conditions in apneic patients during sleep. In Specific Aim 2, we will explore why reflex responses to hf-TTI administration modulate upper airway collapsibility differently during (a) stable and (b) transitional sleep. In Specific Aim 3, we build upon insights gained from the earlier aims, and propose two novel hf-TTI strategies for ventilating (a) patients with severe upper airway obstruction and (b) animals with varying degrees of upper airway obstruction during sleep. Experiments are proposed initially to optimize upper airway function and ventilation in apneic patients during sleep. Complementary studies in animals are proposed to extend our insights to humans with lesser degrees of upper airway obstruction during sleep. Standard physiologic recording methods will be utilized to perform these experiments. The proposed experiments will serve to further our understanding of the underlying pathogenesis of upper airway obstruction as well as build the foundation for novel approaches to support ventilation in sleeping apneic patients.